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Energy Expenditure and Adaptive Responses to an Acute Hypercaloric Fat Load in Humans with Lipodystrophy

Departments of Clinical Biochemistry and Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Stephen O’Rahilly, Department of Clinical Biochemistry and Medicine, Level 4, Box 232, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk.

Humans respond to an acute excess of ingested energy by storing the surplus energy as triglyceride in white adipose tissue. To study the energetic response to acute overfeeding in human subjects with limited adipose tissue capacity, we recruited seven subjects with lipodystrophy and seven lean healthy controls. Total fat mass was approximately 70% lower in lipodystrophic subjects (mean, 6.1 kg) than in body mass index-matched lean controls (mean, 22.0 kg). Energy expenditure and macronutrient oxidation rates were assessed in chamber calorimeters on two separate occasions for 40 h, during which time subjects consumed either an energy-balanced diet or a diet incorporating 30% excess energy as fat. On the energy-balanced diet, total daily energy expenditure and basal metabolic rate were linearly associated with lean mass in both groups (r² = 0.83) and were not significantly different between groups when corrected for lean mass. In response to the fat challenge, total energy expenditure did not increase significantly in healthy controls (9,472 ± 1,069 to 9,724 ± 1,114 kJ/d; P = 0.189). Substrate oxidation results confirm that excess fat was predominantly stored. In contrast, lipodystrophic subjects significantly increased total daily energy expenditure (11,081 ± 1,226 to 11,730 ± 1,374 kJ/d; P < 0.005). This was largely attributable to a 29% increase in fat oxidation. Thus, subjects with lipodystrophy uniquely respond to an acute hypercaloric load with a higher energy expenditure increment and by increasing fat oxidation. Insight into the molecular mechanisms responsible for this phenomenon may yield novel therapeutic approaches for obesity.

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